Continuous in-line homogenization process for scale-up production of naltrexone-loaded PLGA microparticles

Abstract

Injectable, long-acting drug delivery systems provide effective drug concentrations in the blood for up to 6 months. Naltrexone-loaded poly(lactide-co-glycolide) (PLGA) microparticles were prepared using an in-line homogenization method. It allows the transition from a laboratory scale to scale-up production. This research was designed to understand how the processing parameters affect the properties of the microparticles, such as microparticle size distributions, surface and internal morphologies, drug loadings, and drug release kinetics, and thus, to control them.The in-line homogenization system was used at high flow rates for the oil- and water-phases, e.g., 100 mL/min and 400 mL/min, respectively, to continuously generate microparticles. A high molecular weight (148 kDa) PLGA at various concentrations was used to generate oil-phases with a range of viscosities and also to compare with a 64 and 79 kDa at a single, high concentration. The uniformity of the microparticles was found to be related to the viscosity of the oil-phase. As the viscosity of the oil-phase increased from 52.6 mPa∙s to 4046 mPa∙s, the span value (a measure of uniformity) increased from 1.24 to 3.1 for the microparticles generated at the homogenization speed of 2000 RPM. Increasing the PLGA concentration from 5.58% to 16.85% showed a corresponding rise in the encapsulation efficiency from 74.0% to 85.8% and drug loading (DL) from 27.4% to 31.7% for the microparticles made with the homogenization speed of 2000 RPM. These increases may be due to a faster shell formulation, enabling PLGA microparticles to entrap more naltrexone into the structure. A higher DL, however, shortened the drug release duration from 56 to 42 days. The changes in morphology of the microparticles during different phases of the in vitro release study were also studied for three types of microparticles made with different PLGA concentrations and molecular weights. As PLGA microparticles went through structural changes, the surface showed raisin-like wrinkled morphologies within the first 10 days. Then, the microparticles swelled to form smooth surfaces. The in-line approach produced PLGA microparticles with a highly reproducible size distribution, DL, and naltrexone release rate.